Field of the Invention
The present invention relates to detection probes and methods of use, and more particularly, related to 19F-labeled bile acid tracer and methods of use to evaluate hepatobiliary and/or gastrointestinal health, enterohepatic circulation, and/or drug interactions.
Description of the Related Art
Bile acids are produced in the liver as end products of cholesterol metabolism. After their synthesis, bile acids are conjugated to glycine or taurine, and secreted into bile by the bile salt export pump (BSEP; ABCB11) and to a lesser extent by the multidrug resistance associated protein 2 (MRP2; ABCC2). Between meals, bile is stored in the gallbladder. In response to a meal, the gallbladder contracts and bile acids are emptied into the duodenum where they increase lipid solubility through micelle formation. Bile acids are passively absorbed throughout the small intestine, as well as actively absorbed by enterocytes in the terminal ileum via the apical sodium-dependent bile acid transporter (ASBT, SLC10A2). After uptake by enterocytes, bile acids are effluxed into the portal circulation by the organic solute transporters (OSTα-OSTβ; SLC51A, SLC51B) and to a lesser extent by multidrug resistance protein 3 (MRP3; ABCC3). At the liver, the bile acids are taken up by hepatocytes via the Na+/taurocholate cotransporting polypeptide (NTCP, SLC10A1) and the organic anion transporting polypeptides (OATPs) for re-secretion into bile. This enterohepatic circulation of bile acids maintains the human bile acid pool between 2-4 g. Bile acids circulate several times daily with less than 10% lost in feces.1,2 
Excess bile acids entering the colon contribute to the symptoms of bile acid malabsorption (BAM) which is characterized by excess fecal bile acids and chronic watery diarrhea and is often misdiagnosed as diarrhea-predominant irritable bowel syndrome (IBS-D).3 BAM is considered responsible for 30-50% of unexplained chronic diarrhea.4,5,6,7 Although BAM can be attributed to ileal resection/damage or rare ASBT mutations, the cause of most cases of idiopathic BAM is unknown. Recent advances in understanding this disease suggest that overproduction of bile acids resulting from deficient fibroblast growth factor (FGF)-19 may be a common feature of BAM.8 FGF19 is part of the mechanism for feedback inhibition of hepatic bile acid synthesis from cholesterol, and regulation of bile acid synthesis is impaired in its absence. This dysregulation leads to hepatic overproduction of bile acids, exceeding the ileal absorptive capacity, thereby increasing colonic exposure and diarrhea.
In the United States, diagnosis of BAM is limited by the lack of sensitive, specific and cost-effective tests. 75Se-homocholic acid-taurine (HCAT), a 75Se-labeled gamma-emitting synthetic bile acid used to measure intestinal uptake of bile acids, is available for use in selected European countries, but has not been approved by the FDA.9 Diagnostic criteria for this test are based on the percentage of 75Se-HCAT retained in the body one week after oral administration. Other methods to diagnose BAM include 14C-taurocholate stool measurement10, 7α-hydroxy-4-cholesten-3-one serum measurement as a biomarker of bile acid formation11, and blood FGF19 measurement12 (inversely related to 7α-hydroxy-4-cholesten-3-one levels). However, these methods are time-consuming, difficult, not readily available, or not validated clinically. Hence, BAM is often diagnosed by administering bile acid sequestrants, such as colesevelam, in a therapeutic trial13,14, an approach that is not FDA-approved for this indication, lacks specificity and has a high rate of false-negative diagnosis.7 
To address these limitations, CA-lys-TFA, a conjugate of trifluoroacetyl-lysine and cholic acid, was previously synthesized and tested for the diagnosis of BAM by using in vivo imaging of the trifluorinated bile acid analogue with 19F magnetic resonance imaging (MRI).15 The CA-lys-TFA was used as a tagged bile for tracking to determine its accumulation in the gallbladder to determine the differentiation between normal and impaired bile acid transport. However, when CA-lys-TFA was used an imaging agent, it was susceptible to bacterial metabolism, that being, removal of its amino acid side chain by choloylglycine hydrolase (CGH), a bacterial bile acid deconjugating enzyme located predominantly in the colon and in smaller amounts in the terminal ileum.15 
Thus, it would be advantageous to provide an imaging probe having the ability to non-invasively assess bile acid transport and diagnose impaired intestinal bile acid uptake, such as BAM, while not being susceptible to bacterial deconjugation by CGH.